ABSTRACT The Department of Veteran's Affairs Health System provides comprehensive health care for veterans returning from conflicts. The incidence of blast traumatic brain injury (TBI) for U.S. veterans has risen considerably since the beginning of the current conflicts in Iraq and Afghanistan. Where injured veterans from previous military conflicts demonstrated primarily focal injuries, a majority of injuries sustained in the current conflicts are blast-induced and are multifocal and polytraumatic in nature. While outcomes from blast TBI are acutely similar to TBI resulting from head impact, a condition commonly sustained during automotive collisions and falls, chronic outcomes may be different. This may indicate a need for Veteran's Affairs clinicians to distinguish between blast and blunt TBI in terms of treatment and rehabilitation. Differences in outcomes between the two mechanisms have not been well defined. The proposed research will incorporate in vivo rodent injury models for blast and blunt trauma mechanisms of TBI to delineate differences in acute, subacute, and chronic outcomes following two levels of mild TBI (i.e., concussion). The blunt trauma injury device induces TBI through pure coronal plane rotational acceleration of the head. The blast injury device induces TBI using a blast overpressure wave created using a compression-driven shock tube. The existing models were developed in our laboratory and are unique in their ability to induce repeatable and recoverable mild TBI without the requirement for invasive surgery. Preliminary testing has demonstrated 100% survivability without cervical spine injury from head rotation or polytrauma typically associated with blast injury. The experimental protocol will expose Sprague Dawley rats to two levels of blast or rotational injury (mild and severe concussion), for a total of five experimental injury groups (including controls). Magnitude of rotational TBI will be modulated by controlling peak head rotational acceleration. Magnitude of blast TBI will be modulated by controlling peak blast overpressure. Injury levels will be equated between the two mechanisms using unconscious times, wherein mean unconscious times will be equal for mild blast and mild rotational TBI and equal for severe blast and severe rotational TBI. Post-injury assessments will incorporate a number of well defined tests to determine the level of anterograde amnesia and spatial learning deficits, retro-grade amnesia, neuromotor deficits, anxiety-related behavior and aggression, adhedonic behavior (i.e., emotionality/depression), brain edema, and neuronal, glial, or white matter pathology. Assessments will be conducted at multiple time points between two and sixty days post-injury. A total of five post-injury assessment sub-groups will be required to avoid confounding effects of different assessments and time points. Therefore, a total of 25 independent groups will be used during the course of the proposed research (five experimental injury groups times five post-injury assessment sub-groups). Statistical analysis using assessment data reported in literature determined a sample size of 15 rats will be required to determine a 1.5-fold or larger difference in the outcome between two treatment groups with 95% confidence. The proposed research will be conducted over a four-year period, with an initial focus on identifying differences between severe blast and severe rotational TBI. Preliminary statistical analyses will be conducted during the course of the proposed research. Pending statistically significant outcomes prior to the completion of all 15 rats per group, other groups (e.g., moderate or super-severe) may be added to the protocol. This research will generate basic science data that will provide the foundation for changes in clinical culture and initiate custom and more effective treatment and rehabilitation protocols for blast and blunt TBI. PUBLIC HEALTH RELEVANCE: NARRATIVE Brain trauma is a major injury resulting from the current conflicts. Returning soldiers that sustained a traumatic brain injury (TBI) undergo rehabilitation and many have lifelong consequences. Of particular difficulty is when the brain trauma is mild. The symptoms may be headaches, fatigue, and memory loss that are often hard to distinguish and relate to a traumatic event. Soldiers in conflict situations may have been exposed to a blast event or a blunt trauma event related to a head impact. The physics of these injury mechanisms are remarkably different. When these types of injuries are low level or mild, symptoms can be very similar, however the long-term outcomes may be different. This proposal seeks to differentiate between these two types of mild TBI mechanisms by using unique experimental animal models. The rodent models employed will quantify the behavioral and physiological differences, if any, between these two types of TBI. The knowledge gained will serve as a scientific basis for rehabilitation specialists who seek specific treatments for veterans.